RMD Open最新文献

Objective: To characterise phenotype and functional profibrotic M2 markers in circulating monocytes and cultured monocyte-derived macrophages (MDMs) from systemic sclerosis (SSc) patients (pts) with progressive interstitial lung disease (ILD) (prog-ILD), non-progressive ILD (no-prog-ILD) and without ILD (no-ILD).

Methods: Fifty-five SSc pts and 20 age-matched healthy controls were evaluated. In 36 SSc pts, circulating monocytes expressing toll-like receptor-4 (TLR4, M1 marker) and M2 phenotype markers (CD204, CD206, CD163) were detected by flow cytometry. Moreover, MDMs of 29 SSc pts were analysed by quantitative real-time PCR and Western blotting for gene expression and protein synthesis with regard to the production of profibrotic mediators: transforming growth factor-ß1 (TGFß1), Mer tyrosine kinase receptor (MerTK) and arginase-1 (ARG1). Interleukin-6 and 4 (IL6, IL4), as well as C-C motif chemokine ligand 2 and 18 (CCL2/MCP1 and CCL18) from culture medium, were evaluated by enzyme-linked immunosorbent assay (ELISA).

Results: Prog-ILD SSc pts showed a higher percentage of TLR4⁺CD204⁺CD206⁺CD163⁺ monocytes versus no-prog-ILD, and significantly higher compared with no-ILD SSc pts.Interestingly, MDMs from prog-ILD SSc pts showed a significantly higher gene expression and protein synthesis of TGFβ1, and a significantly higher protein synthesis of MerTK, CD206, IL4 and CCL18 compared with no-prog-ILD SSc pts. Finally, gene expression and protein synthesis of TGFβ1, TLR4, CD206, CD163, ARG1, MerTK and IL6 were significantly increased in prog-ILD SSc versus no-ILD SSc MDMs.

Conclusions: Cultured MDMs from circulating monocytes in SSc pts with prog-ILD show markedly increased profibrotic biomarkers and mediator expression, indicating an enhanced fibrotic phenotype compared to non-prog and no-ILD SSc pts.

Objective: We explored associations between endogenous oestrogens, coronary atherosclerosis and cardiovascular risk in rheumatoid arthritis (RA). We interrogated whether these relationships varied by sex and menopause and reflected differences in inflammation and lipoprotein functions influencing cell cholesterol homeostasis.

Methods: CT angiography evaluated atherosclerosis in 140 patients without cardiovascular disease from a single-centre observational cohort. Serum estrone and 17-b-oestradiol were measured with Elisa. Serum cholesterol loading capacity (CLC) on macrophages, which enhances atherosclerosis, was measured in THP-1 monocyte-derived macrophages. High-density lipoprotein cholesterol efflux capacity from macrophages via ATP-binding-cassette-A1 (ABCA1-CEC) and G1 transporters (ABCG1-CEC), which attenuates atherogenesis, was assessed in J774 macrophages and Chinese hamster ovary cells.

Results: Estrone and estradiol associated with higher coronary artery calcium score (p-for-interaction≤0.023) and estradiol with more coronary plaques (p-for-interaction=0.048) in males but not females. Estrone was linked to fewer plaques in premenopausal women (p-for-interaction=0.043), while both estrone and estradiol were associated with more plaques in postmenopausal women. Estrone is associated with higher proatherogenic cytokine levels in males and in postmenopausal women, but lower levels in premenopausal women. Moreover, estrone was inversely associated with ABCA1-CEC (p-for-interaction=0.008) and ABCG1-CEC (p-for-interaction=0.040) in males, while estradiol was positively associated with CLC (p-for-interaction=0.044) and inversely with ABCA1-CEC (p-for-interaction=0.010) in males. Estrone, but not estradiol, was inversely associated with cardiovascular risk (adjusted HR 0.43 (95% CI 0.21 to 0.86) per SD increase), particularly among premenopausal women (p-for-interaction=0.015).

Conclusion: Sex and reproductive status modified the effect of endogenous oestrogens on atherosclerosis in RA and their associations with inflammation and lipoprotein functions impacting on cholesterol homeostasis.

Objective: The objective of this study is to assess the association between childhood exposure to pets and farm animals and the risk of developing rheumatoid arthritis (RA) in adulthood, using data from a large prospective cohort.

Methods: We analysed 78 473 women from the Etude Epidémiologique auprès des femmes de la Mutuelle générale de l'Education Nationale cohort, among whom 698 incident cases of RA were identified and validated. Childhood exposure to domestic pets (cats, dogs) and farm animals, as well as the age at first exposure, was self-reported by participants using predefined categorical options (eg, never, <1 year, 1-2 years, etc). HRs were estimated using Cox models, with confounders selected via directed acyclic graphs.

Results: Early exposure to pets (cats/dogs) between the ages of 1 year and 2 years compared with no exposure was associated with a lower risk of RA (adjusted HR (aHR) 0.57, 95% CI 0.34 to 0.95), regardless of smoking status. However, no association was observed with pet exposure at earlier (<1 year) or later ages. Conversely, exposure to farm animals (cows, sheep, pigs) during childhood was borderline associated with an increased risk of RA (aHR 1.26, 95% CI 1.00 to 1.59), irrespective of age at exposure.

Conclusion: How and when children are exposed to animals could affect the risk of developing RA. Our results suggest a potential inverse association restricted to pet exposure at ages 1-2 years, but not at other ages, whereas exposure to farm animals was positively associated. These findings should be interpreted cautiously and warrant further investigation.

Trial registration number: NCT03285230.

Objective: To assess the long-term effect of bimekizumab, a dual inhibitor of IL-17A and IL-17F, on patient-reported symptoms, function and health-related quality of life (HRQoL) in patients with axial spondyloarthritis (axSpA) from phase 3 studies and their open-label extension.

Methods: BE MOBILE 1 (non-radiographic-axSpA) and 2 (radiographic-axSpA) comprised 16-week double-blind placebo-controlled and 36-week maintenance periods. From week 16, all patients received subcutaneous bimekizumab 160 mg every 4 weeks. At week 52, eligible patients could enrol in the open-label extension BE MOVING and continue bimekizumab treatment. Spinal pain (rated on a numerical rating scale from 0 (no pain) to 10 (maximum pain)), morning stiffness (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) average of Q5/6), fatigue (BASDAI Q1; Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale), sleep quality (Medical Outcomes Study (MOS) Sleep Scale Index II), physical function (Bath Ankylosing Spondylitis Functional Index (BASFI)) and HRQoL (36-Item Short Form Survey (SF-36) physical component summary (PCS)/mental component summary (MCS); Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire) were reported to week 104.

Results: In total, 494/586 (84.3%) patients entered BE MOVING at week 52; 456 completed week 104. Patients reported substantial changes from baseline to week 104 in total spinal pain (-4.3), nocturnal spinal pain (-4.3), morning stiffness (-4.3) and fatigue (BASDAI Q1: -3.4; FACIT-Fatigue: +9.9). Over half reported total and nocturnal spinal pain scores ≤3 at week 104. Similar improvements to week 104 were shown in sleep (MOS-Sleep Scale: +10.2), physical function (BASFI: -2.9) and HRQoL (SF-36 PCS: +12.4; ASQoL: -5.6).

Conclusions: Bimekizumab treatment resulted in sustained improvements in patient-reported symptoms and their impacts across the full disease spectrum of axSpA over 2 years, underscoring its long-term potential for improving patients' daily lives.

Trial registration numbers: NCT03928704, NCT03928743, NCT04436640.

Objective: To investigate complement system activation and complement protein levels in relation to radiographic progression in axial spondyloarthritis (axSpA) within a longitudinal randomised controlled trial (RCT) of radiographic axSpA patients initiating tumour necrosis factor inhibitor (TNFi) therapy.

Methods: Serum samples from 96 patients with active radiographic axSpA in the multicentre RCT CONSUL were analysed by immunoassays for complement activation, that is, C3dg and complement proteins (MBL, CL-L1, M-, H- and L-ficolin; MASP-1,-2 and -3; and MAp44) before and after 108 weeks of TNF inhibitor therapy with golimumab.

Results: Baseline serum levels of total complement activation, that is, C3dg and lectin pathway activating protease MASP-1 were elevated in patients with new bone formation (new syndesmophytes and/or growth of existing syndesmophytes) after 2 years of follow-up, whereas baseline MASP-3 levels were decreased. Assessed by univariate logistic regression, baseline levels of MASP-1, MASP-3 and C3dg were associated with the development of new bone formation and remained significant in a corresponding multivariate logistic regression analysis. At follow-up, serum levels of C3dg and complement lectin pathway initiator L-ficolin were elevated in patients with new bone formation, and C3dg remained significant in a corresponding multivariate logistic regression analysis.

Conclusions: Complement activation marker C3dg, MASP-1 and MASP-3 levels before TNFi therapy predicted new bone formation after 2 years of follow-up among axSpA patients with a high risk of radiographic progression. Furthermore, levels of L-ficolin and C3dg at follow-up were elevated in axSpA patients with new bone formation. Our findings support an association between activation of the complement system and radiographic spinal progression in patients with axSpA.

Objectives: Activated synovial fibroblasts play a key role in rheumatoid arthritis (RA). Positron emission tomography-CT (PET-CT) using ^68gallium-labelled fibroblast activation protein inhibitor (FAPI) allows the detection of FAP-expressing activated fibroblasts in humans in vivo. Herein, this study aimed to investigate whether fibroblast activation already occurs in the pre-clinical phase of RA and whether it is associated with the development of clinical disease.

Methods: ⁶⁸Ga-FAPI-46 PET-CT was performed in individuals positive for anti-citrullinated protein antibodies (ACPAs) with clinically suspect arthralgia without present or past signs of joint swelling or present or past anti-rheumatic therapy. All participants underwent structured clinical and laboratory evaluations and were followed for the development of RA. Synovial FAPI uptake was quantified and related to demographic characteristics, joint tenderness, ACPA levels and RA development.

Findings: Eighteen RA-at-risk individuals (male/female: 7/11; mean age, 47 (SD 14) years) underwent ⁶⁸Ga-FAPI-46 PET-CT and were followed for a median of 42 weeks. Five participants (28%) developed RA with a median of 12 weeks (IQR, 11-20), whereas 13 remained disease-free. Total lesion FAPI-uptake (TL-FAPI) was a significant predictor of RA development (HR 4.58, 95% CI 1.38 to 15.22, p=0.013). Increasing TL-FAPI at the joint level was also associated with tenderness (isk ratio 1.14, 95% CI 1.08 to 1.22, p=0.001).

Conclusions: The findings in this small RA-at-risk cohort suggest that synovial fibroblast activation occurs early in the disease process of RA and is associated with an increased risk for clinical RA onset. These results warrant further research on FAPI-PET-CT to improve risk assessment for clinical RA onset.

Objectives: To identify in a genetically susceptible population individuals at higher risk of developing rheumatoid arthritis (RA) using a classification approach combining known epidemiological risk factors, serological biomarkers, genetics, clinical signs and symptoms.

Methods: We used data from the prospective SCREEN-RA (Evaluation of a SCREENing strategy for Rheumatoid Arthritis) cohort of 1540 first-degree relatives of RA patients (RA-FDRs). The primary outcome was the development of RA. Additionally, we used seropositive inflammatory arthritis (IA) as a secondary outcome for exploratory analyses. Balanced random forest (BRF) models were fit and evaluated through fivefold cross-validation to avoid overfitting. We chose a classification threshold that targeted high sensitivity.

Results: After a mean follow-up of 7.1 years, 27 participants developed RA and 126 developed seropositive IA. The BRF demonstrated moderate predictive performance, characterised by high sensitivity (≥0.85) but modest specificity. Rheumatoid factors (RFs) had the highest importance in RA prediction, followed by symptoms of 'clinically suspected arthralgia' (CSA) scale. Age, gender and anti-RA33 autoantibodies were the main variables for the prediction of seropositive IA.

Conclusions: Overall, the results demonstrate that predicting RA by combining genetics, serological biomarkers, epidemiological risk factors and clinical signs is promising, although model generalisation remains challenging. The low prevalence of RA in the cohort complicates the development of highly accurate prediction models. Future efforts should focus on including external validation and potentially incorporating additional biomarkers to enhance the sensitivity and overall performance of the predictive tests.

Background and aim: Juvenile idiopathic arthritis-associated uveitis (JIAU) is a potentially blinding condition beginning in childhood. Flare-ups may occur throughout life, leading to cumulative ocular damage. This systematic review aimed to summarise the latest evidence on long-term ocular damage in adults with JIAU, focusing on studies published in the past 20 years.

Methods: The review protocol was registered in PROSPERO (ID 1033522). We included human studies on JIAU with at least 5 years of follow-up and/or young people ≥18 years old, published after 2000. Study quality was assessed using the Newcastle-Ottawa Scale. We extracted the cumulative incidence of complications and performed a meta-analysis to obtain pooled estimates (PE), assess heterogeneity, sensitivity, robustness and reporting bias using R packages.

Results: 22 retrospective or cohort studies were eligible, encompassing 2208 long-term JIAU cases. Study quality was rated as good in 10, fair in 7 and poor in 5. Despite high heterogeneity (p<0.01), sensitivity analyses supported robustness. Evidence of reporting bias was found for severe visual impairment and cataract. The pooled incidence of severe visual impairment was 16.6% (95% CI 9.9% to 22.6%) at approximately 18 years. Cataract was the most frequent complication (PE 44.3% (95% CI 27.5% to 61.7%)), followed by glaucoma, synechiae, band keratopathy and hypotony. In cohorts with >50% biologic exposure, PE were numerically lower.

Conclusion: Long-term prevalence and cumulative incidence of JIAU complications may persist in adulthood, with >10% developing severe visual impairment despite biologic therapy.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotising vasculitis characterised by tissue and blood hypereosinophilia. Cardiac involvement has previously been identified as the most significant predictor of mortality.

Objective: To identify and characterise previously untreated patients with EGPA and their cardiac manifestations at disease onset.

Methods: A retrospective monocentre study was conducted on 103 patients. Upon patient presentation, detailed multidisciplinary physical evaluations and laboratory diagnostics were performed. Cardiac events were defined as EGPA-related abnormalities in ECG, echocardiography, cardiac MRI, invasive coronary angiography or cardiac histopathology.

Results: Cardiac manifestations were diagnosed in 36 of 103 patients with EGPA (35%). Patients with EGPA with cardiac involvement (EGPA-CI) exhibited typical symptoms of EGPA concomitant with elevated cardiac biomarkers. Pericarditis (77%), cardiomyopathy with cardiac failure (55%) and definite myocarditis (36%) were the most common diagnoses, which in some cases resulted in cardiogenic shock (14%) or cardiac arrest (6%). Vasospastic coronary arteries causing myocardial infarctions were identified as a life-threatening cardiac manifestation in 8% of patients with EGPA-CI. Overall, patients with EGPA-CI presented with significantly higher disease activity and worse prognosis, with elevated median eosinophilic count and C-reactive protein levels.

Conclusions: Cardiac involvement is a common initial manifestation of EGPA and is associated with elevated systemic disease activity. In addition to pericarditis and myocarditis, coronary vasospasms were identified as a rare and severe manifestation of EGPA that may mimic myocardial infarction. Consequently, at the early stage of disease, patients may present with advanced cardiac impairment, emphasising the necessity of prompt diagnostic and therapeutic intervention to positively affect prognosis.